Antiviral Res 2011 Dec;92 (3): 424-33. [IF:4.439]
Exploring the molecular basis of dsRNA recognition by NS1 protein of influenza A virus using molecular dynamics simulation and free energy calculation.
Pan D , Sun H , Shen Y , Liu H , Yao X .
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
兰州大学药学院
Abstract
The frequent outbreak of influenza pandemic and the limited available anti-influenza drugs highlight the urgent need for the development of new antiviral drugs. The dsRNA-binding surface of nonstructural protein 1 of influenza A virus (NS1A) is a promising target. The detailed understanding of NS1A-dsRNA interaction will be valuable for structure-based anti-influenza drug discovery. To characterize and explore the key interaction features between dsRNA and NS1A, molecular dynamics simulation combined with MM-GBSA calculations were performed. Based on the MM-GBSA calculations, we find that the intermolecular van der Waals interaction and the nonpolar solvation term provide the main driving force for the binding process. Meanwhile, 17 key residues from NS1A were identified to be responsible for the dsRNA binding. Compared with the wild type NS1A, all the studied mutants S42A, T49A, R38A, R35AR46A have obvious reduced binding free energies with dsRNA reflecting in the reduction of the polar and/or nonpolar interactions. In addition, the structural and energy analysis indicate the mutations have a small effect to the backbone structures but the loss of side chain interactions is responsible for the decrease of the binding affinity. The uncovering of NS1A-dsRNA recognition mechanism will provide some useful insights and new chances for the development of anti-influenza drugs.
摘要:
流感大流行的频繁爆发和有效抗流感药物的缺乏更强调了新的抗病毒药物研发的急切性。流感A病毒上，与双链RNA表面结合的非结构蛋白1（NS1A）是一个潜在的药物作用靶点。深入了解NS1蛋白和dsRNA之间的相互作用对抗流感药物的研发有重要价值。我们使用分子动力学模拟和自由能计算的方法，来描述和研究dsRNA和NS1蛋白之间的相互作用的主要特征。基于自由能计算，我们发现分子内的范德华键和非极性溶剂在结合过程中提供主要的驱动力量。同时，NS1蛋白识别dsRNA的17个主要作用点也被明确指出。与野生型NS1蛋白相比，突变型S42,T59,R38R35,R46等蛋白因极性和/或非极性之间的相互作用降低而使与dsRNA结合自由能明显降低。另外，结构和能量分析表明突变的蛋白对骨干结构有一点影响，这是因为负责结合位点定位的侧链间相互作用的丧失而引起的。NS1蛋白和dsRNA之间相互作用机制的发现为抗流感药物的研发提供了一些有用的信息。
